Novel KNDy receptor drugs may be the future of treating menopausal vasomotor symptoms
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A group of novel agents could change the way providers care for women experiencing moderate or severe vasomotor symptoms.
During a presentation at the North American Menopause Society annual meeting, Susan D. Reed, MD, MPH, professor and vice chair of the department of obstetrics and gynecology at the University of Washington School of Medicine in Seattle, said new drugs targeting the kisspeptin/neurokinin B/dynorphin [KNDy] neuron receptor complex have proven to be effective at treating hot flashes and other menopause symptoms in early trials.
“The KNDy neuron manipulation ... is really exciting and holds great promise for rapid and highly effective amelioration of hot flashes, up to 80%, and improvement in other menopausal symptoms,” Reed said during the presentation. “We’re still looking at safety in phase 3 trials. For now, the selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and GABAergics are the best frontline, nonhormonal options with a moderate effect.”
Reed spoke with Healio about vasomotor symptoms, the novel drugs currently in development, and the impact those drugs may have in the future.
What exactly is happening when a woman experiences a hot flash?
Reed : When a woman experiences a hot flash, her brain actually thinks that she needs to vasodilate to let off heat, and as she vasodilates, she has a sensation of a “hot flash” or a dissipation of heat and warmth. It’s her brain telling her that she needs to cool off, but at a core temperature that she otherwise would not be doing that.
What role does the KNDy neuron complex play in hot flashes?
Reed : What happens at menopause is that these neurons have just been cooking along up there, doing their thing. They interact with the GnRH pulse generator that helps with orchestration of ovulation. But when estrogen levels fall, this whole complex of neurons goes into hyperdrive, and their impulses spill over into the immediately adjacent hypothalamic brain region – the thermoregulatory center. When estrogen falls, it causes this KNDy neuron complex to just basically go bonkers. It’s like turning on a bazillion fire hydrants and the fire hydrants spill over into the thermoregulatory center and cause dysregulation. We know this because of autopsy studies that have looked at this area in the brain in postmenopausal women compared to premenopausal women, and this area in the brain in postmenopausal women is basically on fire, with massive hypertrophied neurons. These studies were started by Naomi E. Rance, MD, PhD, at the University of Arizona Health Sciences in the 1980s, but our understanding has really come to fruition around these ideas in the last decade. It’s pretty cool because we literally get at the true etiology of a hot flash, which we never really understood before.
Estrogen therapy is commonly prescribed for women with bothersome hot flashes. What might influence a choice between this hormone option and nonhormonal options?
Reed : Some women cannot take hormones for medical reasons. A great example is a woman with breast cancer or another example is someone who has a a clotting disorder. Those conditions are hormonally driven, and for example, taking estrogen in a woman with breast cancer puts her at a higher risk for breast cancer recurrence. Other women may have a family history that’s concerning, and they don’t want to take hormones, or they took hormones before and they didn’t like the way they felt. It’s just an overall preference for the type of medication a woman wants to take.
What are some of the successful, nonhormone therapies that have preceded KNDy neuron targeting?
Reed : The group of selective serotonin reuptake inhibitor and serotonin-norepinephrine reuptake inhibitor medications have been shown to be beneficial in doses that are almost across the board lower than you would use for a mood disorder. Because they are low dose, they tend to have very low side effect profiles, but they’re not as effective as standard dose hormonal therapies. They’re good for women with mild to moderate hot flashes, but they aren’t necessarily as great for women with moderate to severe hot flashes.
What are some of the novel drugs in development, how effective are they, and what are some of the adverse effects?
Reed : Initial studies that came out in 2017 were looking at a product called pavinetant (Millendo Therapeutics), or MLE4901, and that drug development stopped because of findings of increased abnormalities in liver function that were concerning. We now are seeing a development of ESN364, which is fezolinetant (Astellas), also an NK3 receptor antagonist just like pavinetant. Again, we’re seeing some changes in liver function but not to the degree that the company feels they should stop drug development. They’re in phase 3 clinical trials, which means they’re looking really carefully at safety. If concerns regarding liver safety remain, it may be that baseline and then careful follow up liver function testing will be warranted for women choosing these therapies if FDA-approved. But the drug looks good as far as treatment, 80% effectiveness and overall well-tolerated. The phase 3 trial results on 1,740 women studied for one year are expected in 2021, with probable publication in 2022.
Another exciting new drug is a dual NK1 and NK3 receptor antagonist, whereas liver function abnormalities have been observed in the therapeutics that are NK3 receptor antagonist specific. This dual antagonist, called NT-814 (Bayer), looks better as far as liver function abnormalities, but has only just completed the relatively small phase 2 clinical trials. A phase 3 study is planned to start early 2021. These novel nonhormonal KNDy neuron complex therapeutics are truly exciting in that they target the top of the pyramid of the menopausal symptom causal pathway and are a class of drugs the likes of which we have never seen in our field before.
If approved, how could these novel drugs change the way postmenopausal women receive treatment for hot flashes?
Reed : Treatment will change dramatically, in that these drugs would be safe for breast cancer survivors and would be incredibly effective. For women with very burdensome symptoms, they work really well. They work fast, so within days women are feeling an effect. This is the greatest thing since sliced bread, and only the trials will tell us if indeed it’s going to be that good.
What are the most important things providers should look for when treating women with hot flashes?
Reed : It’s really important that we look towards individualizing treatments for our patients, and we need to look at how they prioritize their symptoms. There’s a symptom complex that occurs for patients when their reproductive hormones fall dramatically, and we need to target the area that’s most bothersome for the patient sitting in front of you. We are starting to have the tool kits available to be able to do that. If our breast cancer survivors have horrific hot flashes and they’re not sleeping well, it may be that these new KNDy neuron complex therapeutics are going to be an amazing breakthrough for them. Thinking about the individual and what’s a good choice for her and giving her an option is where we’re headed. It’s good to see the field evolve and give our patients more effective safe options.
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Reed SD. Recent advances in the treatment of vasomotor symptoms — nonhormonal therapies. Presented at: North American Menopause Society Annual Meeting; Sept. 28-Oct. 3, 2020 (virtual meeting).
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